Decrease In Cavity Size Research Articles

Pre-Clinical Assessment of Roflumilast Therapy in a Thoracic Model of Spinal Cord Injury.

The failure of axons to regenerate after a spinal cord injury (SCI) remains one of the greatest challenges in neuroscience. The initial mechanical trauma is followed by a secondary injury cascade, creating a hostile microenvironment, which not only is not permissive to regeneration but also leads to further damage. One of the most promising approaches for promoting axonal regeneration is to maintain the levels of cyclic adenosine monophosphate (cAMP), specifically by a phosphodiesterase-4 (PDE4) inhibitor expressed in neural tissues. Therefore, in our study, we evaluated the therapeutic effect of an FDA-approved PDE4 inhibitor, Roflumilast (Rof), in a thoracic contusion rat model. Results indicate that the treatment was effective in promoting functional recovery. Rof-treated animals showed improvements in both gross and fine motor function. Eight weeks post-injury, the animals significantly recovered by achieving occasional weight-supported plantar steps. Histological assessment revealed a significant decrease in cavity size, less reactive microglia, as well as higher axonal regeneration in treated animals. Molecular analysis revealed that IL-10 and IL-13 levels, as well as VEGF, were increased in the serum of Rof-treated animals. Overall, Roflumilast promotes functional recovery and supports neuroregeneration in a severe thoracic contusion injury model and may be important in SCI treatment.

Levetiracetam treatment leads to functional recovery after thoracic or cervical injuries of the spinal cord

Spinal cord injury (SCI) leads to dramatic impairments of motor, sensory, and autonomic functions of affected individuals. Following the primary injury, there is an increased release of glutamate that leads to excitotoxicity and further neuronal death. Therefore, modulating glutamate excitotoxicity seems to be a promising target to promote neuroprotection during the acute phase of the injury. In this study, we evaluated the therapeutic effect of a FDA approved antiepileptic drug (levetiracetam-LEV), known for binding to the synaptic vesicle protein SV2A in the brain and spinal cord. LEV therapy was tested in two models of SCI—one affecting the cervical and other the thoracic level of the spinal cord. The treatment was effective on both SCI models. Treated animals presented significant improvements on gross and fine motor functions. The histological assessment revealed a significant decrease of cavity size, as well as higher neuronal and oligodendrocyte survival on treated animals. Molecular analysis revealed that LEV acts by stabilizing the astrocytes allowing an effective uptake of the excess glutamate from the extracellular space. Overall, our results demonstrate that Levetiracetam may be a promising drug for acute management of SCI.

Antiplane Fracture Problem of Three Nanocracks Emanating from an Electrically Permeable Hexagonal Nanohole in One-Dimensional Hexagonal Piezoelectric Quasicrystals

Based on the Gurtin-Murdoch surface/interface model and complex potential theory, by constructing a new conformal mapping, the electrically permeable boundary condition with surface effect is established, and the antiplane fracture problem of three nanocracks emanating from a hexagonal nanohole in one-dimensional hexagonal piezoelectric quasicrystals with surface effect is studied. The exact solutions of the stress intensity factor of the phonon field and the phason field, the electric displacement intensity factor, and the energy release rate are obtained under the two electrically permeable and the electrically impermeable boundary conditions. The numerical examples show the influence of surface effect on the stress intensity factors of the phonon field and the phason field, the electric displacement intensity factor, and the energy release rate under the two boundary conditions. It can be seen that the surface effect leads to the coupling of the phonon field, phason field, and electric field, and with the decrease of cavity size, the influence of surface effect is more obvious.

Anti-plane problem of nano-cracks emanating from a regular hexagonal nano-hole in one-dimensional hexagonal piezoelectric quasicrystals**Project supported by the National Key R&D Program of China (Grant No. 2017YFC1405605), the Innovation Youth Fund of the Ocean Telemetry Technology Innovation Center of the Ministry of Natural Resources, China (Grant No. 21k20190088), the Natural Science Foundation of Inner Mongolia, China (Grant No. 2018MS01005), and

By constructing a new conformal mapping function, we study the surface effects on six edge nano-cracks emanating from a regular hexagonal nano-hole in one-dimensional (1D) hexagonal piezoelectric quasicrystals under anti-plane shear. Based on the Gurtin–Murdoch surface/interface model and complex potential theory, the exact solutions of phonon field, phason field and electric field are obtained. The analytical solutions of the stress intensity factor of the phonon field, the stress intensity factor of the phason field, the electric displacement intensity factor and the energy release rate are given. The interaction effects of the nano-cracks and nano-hole on the stress intensity factor of the phonon field, the stress intensity factor of the phason field and the electric displacement intensity factor are discussed in numerical examples. It can be seen that the surface effect leads to the coupling of phonon field, phason field and electric field. With the decrease of cavity size, the influence of surface effect is more obvious.

A dilemma over percutaneous catheter drainage or percutaneous needle aspiration as first-line management of liver abscess

Background: The aim of the study was to evaluate the clinical presentation and to investigate the effectiveness of percutaneous catheter drainage in comparison to needle aspiration in the treatment of liver abscesses of size more than 5 cm in diameter. Material and Methods: This was a prospective randomized comparative study of 60 patients, presented in outpatient and admitted at the hospital, randomized equally into two groups, percutaneous needle aspiration and percutaneous catheter drainage. The effectiveness of either treatment was measured in terms of duration of hospital stay, days to achieve clinical improvement and total/near total resolution of abscess cavity. Independent t- test was used to analyze these parameters. Results: Percutaneous catheter drainage was successful in all the 30 cases. On the other hand, USG guided percutaneous needle aspiration was successful only in 24 of 30 patients (P=0.005). Out of these 24 patients successfully treated, 6 patients required only one aspiration, 12 required two aspirations, and 6 required three aspirations. The 6 patients who did not show clinical improvement and / or decrease in cavity size despite 3 aspirations were taken as failures. In the PNA group, on comparing the cavity volumes the mean cavity volume in those who were successfully treated was 200 ml which was significantly less than those failing treatment; the mean volume being 400 ml. The patients in PCD group showed earlier clinical improvement (P=0.043) and decrease in abscess cavity volume (P=0.001) as compared to those who underwent PNA. In the present study, the success rate was significantly better in percutaneous catheter drainage group (P=0.005) than needle aspiration. The patients in percuaneous catheter drainage group showed earlier clinical improvement (P=0.043) as compared to those who underwent percutaneous needle aspiration. Conclusion: In the present study, percutaneous catheter drainage is found to be more effective than percutaneous needle aspiration for large liver abscesses of size 5 cm or more in diameter. The clinical improvement is also faster in PCD group than PNA group of the present study.

Dissipative Particle Dynamics Simulation on Vesicles Self-Assembly Controlled by Terminal Groups.

Block copolymer vesicles have been widely used in the field of drug delivery, microreactors, and cell membrane mimetics. Introducing terminal groups to the block copolymer can control the structures of vesicles, which is important for improving the application of vesicles. In this paper, the effects of terminal groups on the structure of vesicles were studied by dissipative particle dynamics simulation. We considered different locations, hydrophobicity, and numbers of terminal groups. When the terminal group located at the end of a hydrophobic block, the increase of wall thickness and the decrease of cavity size of vesicles were observed with the hydrophobicity of the terminal group increasing. In contrast, when the terminal group located at the end of the hydrophilic block, with the hydrophobicity of terminal groups increasing, the vesicular cavity size increased but the wall thickness of vesicles remained nearly unchanged. Finally, increasing the number of terminal groups lead to a decrease of cavity size and an increase of wall thickness of vesicles. The hydrophobic changes of polymer molecules are regarded as the origin of the structural changes of vesicles. This simulation study supplies a potential approach that controls the structures of vesicles and is expected to facilitate its further applications.

Effects of Non-native Interactions on Frustrated Proteins Folding under Confinement.

In vitro, kinetically significant non-native interactions have been identified experimentally during the folding of proteins Im7, Im9, and A39V/N53P/V55L Fyn SH3 domain. To understand the role of non-native interactions on the folding of some frustrated proteins in chaperone, we employed native-centric models with and without additional transferable, sequence-dependent non-native hydrophobic interactions to comparatively study the folding behaviors of the three proteins confined in spherical cages. Under purely repulsive confinement, as a decrease of cavity size, the non-native interactions increase, especially in the unfolded state, enhancing the roughness of the folding energy landscape. As a result, the increase in native stability for the three proteins by the model incorporated non-native interactions (db + MJ hϕ model) is much smaller than that by the purely native-centric model (desolvation-barrier (db) model); the acceleration of folding simulated by the db + MJ hϕ model is much slower than that via the db model; in particular, the folding rate of Im7 decreases when reducing the cavity size under zero-denaturant condition. The repulsive confinement can also promote formation of specific non-native contacts in the transition state and favor more folding pathways passing through the misfolded state, leading to a higher population of the misfolded intermediate. In an attractive cage, the attractive interactions could inhibit the formation of intrachain non-native contacts and provide alternate folding pathways to the native state so that the population of the misfolded intermediate decreases when increasing the strength of attractive interaction between the substrate protein and cavity wall. This study should be helpful in general to understand how the chaperonins reshape the folding energy landscape of some frustrated proteins.

Decrease in Cavity Size and Oligodendrocyte Cell Death Using Neurosphere-Derived Oligodendrocyte-Like Cells in Spinal Cord Contusion Model

Decrease in Cavity Size and Oligodendrocyte Cell Death Using Neurosphere-Derived Oligodendrocyte-Like Cells in Spinal Cord Contusion Model

Decrease in Cavity Size and Oligodendrocyte Cell Death Using Neurosphere-Derived Oligodendrocyte-Like Cells in Spinal Cord Contusion Model

Background:Oligodendrocyte cell death is among the important features of spinal cord injury, which appears within 15 min and occurs intensely for 4 h after injury, in the rat spinal contusion model. Accordingly, the number of oligodendrocytes progressively reduced within 24 h after injury. Administration of oligodendrocyte-like cells (OLCs) into the lesion area is one of the approaches to counterbalance this condition.Methods:Bone marrow stromal cells were transdifferentiated into neurospheres and then into neural stem cells and later were differentiated into OLCs using triiodothyronine and transplanted into the spinal cord contusion rats. The post-injury functional recovery was explored and compared with the control group using Basso-Beattie-Bresnahan and narrow beam behavioral tests. At the end of 12th week, spinal cord segments T12-L1 were histomorphologically studied by immunohistochemistry.Results:Motor improvement was more obvious during 2nd to 4th weeks and got less prominent during 4th to 12th weeks. Histomorphometric findings indicated that cavity formation decreased in epicenter of transplantation area in experimental groups in comparison with the control groups.Conclusion:The findings obtained in the present study showed that OLC therapy is a potential approach in the treatment of spinal cord traumatic injuries.

Structural studies on molecular mechanisms of Nelfinavir resistance caused by non-active site mutation V77I in HIV-1 protease.

BackgroundThe human immunodeficiency virus (HIV-1) is a retrovirus causing acquired immunodeficiency syndrome (AIDS), which has become a serious problem across the world and has no cure reported to date. Human immunodeficiency virus (HIV-1) protease is an attractive target for antiviral treatment and a number of therapeutically useful inhibitors have been designed against it. The emergence of drug resistant mutants of HIV-1 poses a serious problem for conventional therapies that have been used so far. Until now, thirteen protease inhibitors (PIs), major mutation sites and many secondary mutations have been listed in the HIV Drug Resistance Database. In this study, we have studied the effect of the V77I mutation in HIV-PR along with the co-occurring mutations L33F and K20T through multi-nanosecond molecular dynamics simulations. V77I is known to cause Nelfinavir (NFV) resistance in the subtype B population of HIV-1 protease. We have for the first time reported the effect of this clinically relevant mutation on the binding of Nelfinavir and the conformational flexibility of the protease.ResultsTwo HIV-PR mutants have been considered in this study - the Double Mutant Protease (DBM) V77I-L33F and Triple Mutant Protease (TPM) V77I-K20T-L33F. The molecular dynamics simulation studies were carried out and the RMSD trajectories of the unliganded wild type and mutated protease were found to be stable. The binding affinity of NFV with wild type HIV-PR was very high with a Glide XP docking score of -9.3 Kcal/mol. NFV showed decreased affinity towards DBM with a docking score of -8.0 Kcal/mol, whereas its affinity increased towards TPM (Glide XP score: -10.3). Prime/MM-GBSA binding free energy of the wild type, DBM and TPM HIV-PR docked structures were calculated as -38.9, -11.1 and -42.6 Kcal/mol respectively. The binding site cavity volumes of wild type, DBM and TPM protease were 1186.1, 1375.5 and 1042.5 Å3 respectively.ConclusionIn this study, we have studied the structural roles of the two HIV-PR mutations by conducting molecular dynamics simulation studies of the wild type and mutant HIV-1 PRs. The present study proposes that DBM protease showed greater flexibility and the flap separation was greater with respect to the wild type protease. The cavity size of the MD-stabilized DBM was also found to be increased, which may be responsible for the decreased interaction of Nelfinavir with the cavity residues, thus explaining the decreased binding affinity. On the other hand, the binding affinity of NFV for TPM was found to be enhanced, accounted for by the decrease in cavity size of the mutant which facilitated strong interactions with the flap residues. The flap separation of TPM was less than the wild type protease and the decreased cavity size may be responsible for its lower resistance, and hence, may be the reason for its lower clinical relevance.

Change in Postsurgical Cavity Size Within the First 30 Days Correlates With Extent of Surrounding Edema

Resection cavity diameter of less than 40 mm is required to be eligible for stereotactic radiosurgery (SRS), after gross total resection of brain metastasis at our institution. Our study evaluates the correlation between vasogenic edema and change in cavity size for 30 days. Cavity size was measured on the postoperative and follow-up magnetic resonance imaging. Vasogenic edema was quantified as the largest axial measurement of T2 hyperintensity surrounding the resection cavity (postoperative magnetic resonance imaging). Thirty-nine resection cavities (37 patients) were reviewed. There was a statistically significant (Pearson coefficient = -0.35; P = 0.02) negative correlation between edema and change in cavity size. An arbitrary cutoff value of a 15-mm edema yielded a sensitivity of 96% and a specificity of 65% (P < 0.001) to predict 10% decrease in cavity size. In patients with cavity size close to the size cutoff for SRS, rescanning closer to the date of SRS should be considered, especially if there is significant edema surrounding the cavity.

Size Dependence of Quick Cavity Filling Behavior in Ultraviolet Nanoimprint Lithography Using Pentafluoropropane Gas

Rapid bubble elimination using pentafuoropropane (CFH2CH2CF3, HFC-245fa, CAS No. 460-3-1) condensing gas is one of the most promising methods to realize ultrahigh-speed ultraviolet nanoimprint lithography (UV-NIL). In this study, we investigated the shrinkage behaviors and elimination time of bubbles for different cavity sizes and resist thicknesses by employing a UV-NIL stepper with a real-time monitoring system. As predicted, a smaller cavity size resulted in a faster filling. Unlike the prediction from an analysis model based on Stefan's equation, a nonlinear decrease in bubble elimination time was observed in accordance with the decrease in cavity size (area). Instead, a linear relationship between bubble elimination time and cavity width was found for a certain range of cavity widths (W). In the cavity width, range from 25 to 340 µm, bubble elimination time was almost proportional to cavity width and could be defined as 0.00145×W (s). When the cavity width was 25 µm, the complete filling time was less than 0.033 s, indicating the potential to realize a ultrahigh-throughput nanopatterning process. Regarding the effect of initial resist thickness on a bubble shrinkage behavior, bubble elimination time tended to increase with the decrease in resist thickness.

A Simple Semiempirical Model for the Effect of Molecular Confinement upon the Rate of Protein Folding

A simple two-state model for the dependence of the rate of folding of a polypeptide confined within a spherical cavity upon the size of the cavity relative to that of the polypeptide is presented. A general prediction of the model is that decreasing the size of the cavity will increase the rate of refolding until the cavity becomes only slightly larger than the native state of the protein, at which point a further decrease in cavity size decreases the rate of refolding. The model qualitatively accounts for the behavior of several previously published simulations of folding within a cavity, as well as recently reported experimental measurements of the relative rate of refolding of each of five proteins encapsulated within wild-type and mutant GroEL-GroES complexes that have been engineered to provide internal cavities with similar surface composition and varying volume.

Effect of four-alpha-helix bundle cavity size on volatile anesthetic binding energetics.

Currently, it is thought that inhalational anesthetics cause anesthesia by binding to ligand-gated ion channels. This is being investigated using four-alpha-helix bundles, small water-soluble analogues of the transmembrane domains of the "natural" receptor proteins. The study presented here specifically investigates how multiple alanine-to-valine substitutions (which each decrease the volume of the internal binding cavity by 38 A(3)) affect structure, stability, and anesthetic binding affinity of the four-alpha-helix bundles. Structure remains essentially unchanged when up to four alanine residues are changed to valine. However, stability increases as the number of these substitutions is increased. Anesthetic binding affinities are also affected. Halothane binds to the four-alpha-helix bundle variants with 0, 1, and 2 substitutions with equivalent affinities but binds to the variants with 3 and 4 more tightly. The same order of binding affinities was observed for chloroform, although for a particular variant, chloroform was bound less tightly. The observed differences in binding affinities may be explained in terms of a modulation of van der Waals and hydrophobic interactions between ligand and receptor. These, in turn, could result from increased four-alpha-helix bundle binding cavity hydrophobicity, a decrease in cavity size, or improved ligand/receptor shape complementarity.